Aging and HIV/AIDS: pathogenetic role of therapeutic side effects

Abstract

The intersection of aging and HIV/AIDS is a looming ‘epidemic within an epidemic.’ This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active anti-retroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies.

Sarcopenia Em Uma Amostra De Indivíduos Infectados Hiv Atendidos a Nível Ambulatorial

“…Ao comparar com o grupo que não estava sob TARV, este não teve diferença estatística. Entretanto, as alterações decorrentes do próprio HIV e a exposição ao TARV podem ter contribuído para sua maior frequência, uma vez que esses pacientes podem desenvolver complicações relacionadas ao envelhecimento prematuro, predispondo a pré-sarcopenia, aumentando o risco de declínio funcional e mortalidade posteriormente 19 . Já é descrito na literatura que alguns medicamentos antirretrovirais podem favorecer fenômenos próprios do envelhecimento, provocando miopatia inflamatória e mialgia, decorrentes da inibição de transcriptase reversa de telomerase e do acúmulo de precursores lamin A, levando à senescência celular 20,21 .…”

Altered Redox Regulation as Cofactor in Comorbidities and Accelerated Aging in HIV Infection Evolution and Antiretroviral Treatment

“…In contrast, there is compelling evidence that these regulatory processes are altered in old organisms [80,82,83].…”

“…Whether HIV itself or the comorbidities associated are most responsible for frailty and other geriatric symptoms is unclear, but it is widely agreed that inflammation related to HIV, other infections such as CMV, and chronic conditions or lifestyle factors plays a major role in driving more rapid aging and increased morbidity and mortality [52,82].…”

An Optimal Control Strategy for HIV Treatment

“…Even though ART has produced undisputed advances in the treatment of HIV infection, it has been argued that the inhibitors that comprise ART may cause adverse effects, see for example [3,13,14]. Hence, one can argue that a compromise should be reached between the benefits obtained from ART and the adverse effects that it may cause.…”